Abstract
Replication fork stalling generates a variety of responses, most of which cause an increase in single-stranded DNA. ssDNA is a primary signal of replication distress that activates cellular checkpoints. It is also a potential source of genome instability and a substrate for mutation and recombination. Therefore, managing ssDNA levels is crucial to chromosome integrity. Limited ssDNA accumulation occurs in wild-type cells under stress. In contrast, cells lacking the replication checkpoint cannot arrest forks properly and accumulate large amounts of ssDNA. This likely occurs when the replication fork polymerase and helicase units are uncoupled. Some cells with mutations in the replication helicase (mcm-ts) mimic checkpoint-deficient cells, and accumulate extensive areas of ssDNA to trigger the G2-checkpoint. Another category of helicase mutant (mcm4-degron) causes fork stalling in early S-phase due to immediate loss of helicase function. Intriguingly, cells realize that ssDNA is present, but fail to detect that they accumulate ssDNA, and continue to divide. Thus, the cellular response to replication stalling depends on checkpoint activity and the time that replication stress occurs in S-phase. In this review we describe the signs, signals, and symptoms of replication arrest from an ssDNA perspective. We explore the possible mechanisms for these effects. We also advise the need for caution when detecting and interpreting data related to the accumulation of ssDNA.
Highlights
DNA replication stress is a significant contributor to genome instability in cancer and other diseases [1,2,3]
This suggests that ultrafine anaphase bridges (UFBs) are threads of single-stranded DNA (ssDNA)
We are poised to explore how replication protein A complex (RPA) integrates its roles as a sensor, a signal, and a repair mediator after replication stress using a fission yeast model organism
Summary
DNA replication stress is a significant contributor to genome instability in cancer and other diseases [1,2,3]. Replication stress regions define chromosome fragile sites (CFS) that are prone to breakage and associated with accumulation of ssDNA [7]. These may contribute to formation of ultrafine anaphase bridges (UFBs) during mitosis. The accumulation of ssDNA is associated with increased rates of clustered point mutations in yeast and cancer cell lines [28]. The second prediction might describe a situation at a DNA double strand break, if a nearby octamer were co-opted to maintain ssDNA stability by balancing its charged surfaces These predictions have not been explored but are potentially important to our understanding of how nucleosomes repopulate replicated DNA. Any histones associated with ssDNA cannot interfere with normal ssDNA metabolism, either because they are restricted to certain regions or structures, or because the nature of the interaction leaves the ssDNA accessible
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